Treatment of hepatitis C using hyperthermia

ABSTRACT

The invention provides a method of treating a patient infected with hepatitis C virus (HCV) comprising raising the core temperature of the patient and then returning the core temperature of the patient to normal at least one time, wherein the core temperature is raised to a temperature range and a duration sufficient to reduce or eliminate the patient&#39;s viral load of HCV.

FIELD OF THE INVENTION

[0001] This invention relates to hyperthermic treatment of hepatitis C.

BACKGROUND OF THE INVENTION

[0002] Injected drug users are the largest group of people withhepatitis C infection. People who received a blood transfusion or kidneytransplant before a diagnostic test became available form another largegroup of those infected.

[0003] Since human immunodeficiency virus (HIV) is also common amonginjected drug users and is transmitted sexually, about forty percent ofHIV infected patients are co-infected with HCV. Various types of HIVsuch as HIV-1 and HIV-2 exist. Hepatitis C virus occurs in six knowngenotypes and more than fifty subtypes. The hepatitis C virus isharbored in the liver and most people infected with HCV eventually willdevelop cirrhosis or liver carcinoma. HCV can cause an acute or chronicinfection. In chronic infection, the infected person can exhibit signsof chronic hepatitis or be a chronic asymptomatic carrier.

[0004] Current treatments for hepatitis C include interferons and otherpharmaceuticals. However, because these treatments are not effective forall patients, improved methods for treating hepatitis C are beingsought.

SUMMARY OF THE INVENTION

[0005] The invention provides a method for treating a patient infectedwith hepatitis C virus (HCV) comprising raising the core temperature ofthe patient and then returning the core temperature of the patient tonormal at least one time. The core temperature is raised to atemperature range, a duration, and a number of times sufficient toreduce or eliminate the patient's viral load of HCV. In anotherembodiment of the invention, the patient is co-infected with the humanimmunodeficiency virus (HIV).

[0006] The invention also provides a method for treating a patientinfected with HCV comprising raising the temperature of the patient'sliver and then returning the temperature of the patient's liver tonormal at least one time. The temperature of the patient's liver israised to a temperature range, a duration, and a number of timessufficient to reduce or eliminate the patient's viral load of HCV.

[0007] It is to be understood that both the foregoing generaldescription and the following detailed description are exemplary andexplanatory and are intended to provide further explanation of theinvention as claimed.

BRIEF DESCRIPTION OF THE DRAWINGS

[0008]FIG. 1 is a simplified perspective view of an apparatus used topractice the invention.

[0009]FIG. 2 is a mechanical diagram showing cannulation sites on ahuman adult.

[0010]FIG. 3 is a simplified diagram of the system illustrated in FIG.2.

[0011]FIG. 4 is a cross-section of a temperature sensor.

[0012]FIG. 5 is a cross-section of a temperature catheter having atemperature sensor positioned at the urinary sphincter muscle with theaid of an inflatable cuff that engages the bladder wall.

[0013]FIG. 6 is a cross-section of temperature catheter having twotemperature sensors, one of which is positioned at the urinary sphinctermuscle with the aid of an inflatable cuff the engages the bladder walland the second of which is positioned in the urine pool.

DETAILED DESCRIPTION OF THE INVENTION

[0014] The invention provides a method for treating a patient infectedwith hepatitis C virus (HCV) comprising raising the core temperature ofthe patient and then returning the core temperature of the patient tonormal at least one time. The core temperature is raised to atemperature range, a duration, and a number of times sufficient toreduce or eliminate the patient's viral load of HCV. “Treating” in thisapplication means raising the core temperature to a temperature range, aduration, and a number to times sufficient to reduce of eliminate thepatient's viral load of HCV.

[0015] “Returning the core temperature of the patient to normal”includes allowing the patient to cool through ambient heat loss andactively cooling the patient. In the examples described below, thepatient is cooled by ambient heat loss and active cooling to atemperature of 39° C. The patient is released from the hospital and thepatient's temperature gradually returns to normal (37° C.) over a periodof a few days. In one embodiment, the core temperature of the patient israised and returned to normal one time. In another embodiment, the coretemperature of the patient is raised and returned to normal two or moretimes. In one embodiment, the core temperature is raised by circulatingthe patient's blood from the patient, through an extracorporeal bloodflow circuit, and back to the patient, wherein the blood returned to thepatient has been heated within the blood flow circuit to an elevatedtemperature range. The patient's blood can be circulated from thepatient through a blood vessel and returned to the patient through ablood vessel. In one embodiment, the patient's blood is circulated fromthe patient through a vein and returned to the patient through a vein.In another embodiment, the patient's blood is circulated from thepatient through an artery and returned to the patient through a vein. Inanother embodiment, the core temperature is raised by inserting aheating element into the patient and the heating element heats thepatient's blood. The heating element can be inserted into a blood vesselof the patient.

[0016] The heating element can be inserted into a central vessel, i.e.,aorta or vena cava, where it can heat the blood passing by andeventually heating the blood to such a degree that the net temperaturegain exceeds the losses due to the normal (physiologic) coolingmechanisms. Over time the body temperature can be raised to apredetermined point and maintained for a predetermined time. The heatingelement can be housed within a sheath or catheter at one or multiplepositions along its length. The sheath or catheter can contain wires,conduits, fiberoptic, or other materials to supply power to the heatingelement. External to the body there could be a plug to connect thesheath or catheter to the control system. The sheath or catheter can betreated to give it antithrombogenic properties. This treatment can bechemical or a high energy corona or plasma discharge in the presence ofa monomeric gas. The method of insertion can be through a cut-down orpercutaneously (Seldinger Technique).

[0017] The heating element's method of heating can be by an electricalheating, radiofrequency, or laser. The heating element should not exceed50° C. at the surface that contacts blood.

[0018] Such a heating element can be used for core heating and can alsobe used for local or regional heating. For example, a percutaneousinsertion into an artery with a hollow sheath or catheter can be made toaccommodate a steering guidewire so the device can be placed into thehepatic artery. A second hollow catheter with a thermistor tip can beplaced, via a venous percutaneous stick, into the hepatic vein for livertemperature.

[0019] Methods which heat the blood to raise the core temperature, suchas extracorporeal whole body hyperthermia, are preferred. However,methods in which the core temperature is raised by other methods such asby infrared radiation, convection, or surface contact such as a heatingblanket can also be used in the method of the invention.

[0020] The core temperature can be raised to a temperature range of from38 to 48° C. , more preferably 38 to 44° C., more preferably 41.8 to42.2° C. The core temperature can be raised for a period of from 2minutes to sixteen hours, a period of from one-half to three hours, aperiod of from one to two hours, a period of from 80 to 100 minutes, orfor 90 minutes. The core temperature can be taken rectally. For purposesof this application, the “core temperature” means rectal temperature.Temperatures other than the rectal temperature can be taken in thepractice of the invention, e.g., esphogeal, bladder, tympanic, orcardiac line temperatures. The relationship between such othertemperatures and the rectal temperature is well known in the art andsuch measurement by other methods will allow determination of the coretemperature as defined herein.

[0021] Recommended exposure times during extracorporeal whole bodyhyperthermia are given in Table 1 below. TABLE 1 Core Temperature (° C.)Exposure (minutes) 39 960 40 480 41 240 42 120 43 60 44 30 45 15 46 8 474 48 2

[0022] The patient's viral load of HCV can be determined at least oncebefore the core temperature has been raised at least one time; at leastonce after the core temperature has been raised and returned to normalat least one time; at least two different times after the coretemperature has been raised and returned to normal at least one time, orcombinations thereof.

[0023] In embodiments of the invention, the patient's viral load of HCVis reduced by 30 percent or more one month after the core temperaturehas been raised and returned to normal at least one time, morepreferably, by 50 percent or more, by 75 percent or more, by 90 percentor more, or by 95 percent or more. In a preferred embodiment, thepatient's viral load of HCV is reduced to less than the sensitivitylevel of a branched DNA signal amplification test (an example of whichis provided below) one month after the core temperature has been raisedand returned to normal at least one time. This determination of thepatient's viral load is made one month after the last of thehyperthermic treatments. In another preferred embodiment, the patient'sviral load of HCV is reduced to less than the sensitivity level of areverse transcriptase-polymerase chain reaction test (an example ofwhich is provided below) one month after the core temperature has beenraised and returned to normal at least one time.

[0024] In embodiments of the invention, the patient's viral load of HCVis reduced by 30 percent or more three months after the core temperaturehas been raised and returned to normal at least one time, morepreferably, by 50 percent or more, by 75 percent or more, by 90 percentor more, or by 95 percent or more. In a preferred embodiment, thepatient's viral load of HCV is reduced to less than the sensitivitylevel of such branched DNA signal amplification test three months afterthe core temperature has been raised and returned to normal at least onetime. In another preferred embodiment, the patient's viral load of HCVis reduced to less than the sensitivity level of such reversetranscriptase-polymerase chain reaction test three months after the coretemperature has been raised and returned to normal at least one time.This determination of the patient's viral load is made three monthsafter the last of the hyperthermic treatments.

[0025] The method of the invention can further comprise treating thepatient with a pharmaceutical indicated for hepatitis C. The efficacy ofa pharmaceutical effective for treatment of HCV in some patients can beincreased when combined with hyperthermia. The method of the inventioncan also comprise treating the patient with a pharmaceutical indicatedfor HCV where such pharmaceutical was not efficacious for stand alonetreatment for HCV and when combined with hyperthermic treatment resultsin the pharmaceutical being efficacious in some patients. The patientcan be treated with a single pharmaceutical effective against hepatitisC or with two or more pharmaceuticals effective against hepatitis C. Thedrug can be administered to the same patient at several points: beforeraising the core temperature of the patient at least one time, while thecore temperature of the patient is raised, and after the coretemperature of the patient has been raised and returned to normal atleast one time, or combinations thereof.

[0026] The pharmaceutical can be selected from interferons, proteaseinhibitors, cytokines, or any combination of antiviral drugs. Thepharmaceutical can be selected from ribavirin, lamivudine, interferonalfacon-1, interferon alfa-2a, interferon alfa-2b, interferon-alfa-n1,thymosin alpha-1, interleukin-2, interferon alpha-n3, ketoprofen,interferon beta-1a, interferon gamma-1b, interleukin-12, histaminedihydrochloride, thymalfasin, zidovudine, didanosine, zalcitabine,stavudine, abacavar, nevirapine, delaviridine, efavirenz, ritonavir,indinavir, nelfinavir, saquinavir, amprenavir, or combinations thereof.In a preferred embodiment, the pharmaceutical can be selected from aninterferon, ribavirin, or lamivudine. In another preferred embodiment,the pharmaceutical is an alpha interferon. The pharmaceutical can alsoinclude antioxidants, non-steroidal anti-inflammatory drugs, and/orreactive oxygen free radical scavengers. Several pharmaceuticals arebeing studied and some are available for treatment of hepatitis C.Commercially available interferons include INFERGEN (interferonalfacon-1, manufactured by Amgen Inc., Thousand Oaks, Calif.),ROFERON-A, (interferon alfa-2a, manufactured by Roche Pharmaceuticals,Nutley, N.J.), INTRON A (interferon alfa-2b, manufactured by ScheringCorporation, Kenilworth, N.J.), and WELLFERON (interferon alfa-n1,manufactured by Glaxo Wellcome Inc., Research Triangle Park, N.C.).Ribavirin (1-β-D-ribofuranosyl-1H-1,2,4-triazole-3-carboximide) incombination with INTRON-A is sold as REBETRON by Schering Corporation.

[0027] The patient infected with HCV might have an acute HCV infectionor a chronic HCV infection. The patient might be co-infected with apathogen. The pathogen might be a virus, a spirochete, or a bacterium.The virus might be a heat labile virus. The heat labile virus might beselected from herpesviruses, hepadnaviruses, togaviruses, flaviviruses,coronaviruses, rhabdoviruses, filoviruses, paramyxoviruses,othomyxoviruses, bunyaviruses, arenaviruses, or retroviruses. The heatlabile virus might be HIV, hepatitis B virus, Ebstein-Barr virus,cytomegalovirus, or varicella-zoster virus. In a preferred embodiment,the heat labile virus is HIV. The spirochete might be from the genustreponema, borrelia, or leptospira. The spirochete might be Treponemapallidum, Treponema pertenue, Treponema carateum, Treponema pallidumendemicum, Borrelia burgdorferi, Borrelia hermsii, or Leptospirainterrogans. The bacterium might be an aerobic or anaerobic bacterium.

[0028] The invention also provides a method for treating a patientinfected with hepatitis C virus comprising raising the temperature ofthe patient's liver and then returning the temperature of the patient'sliver to normal at least one time. The temperature of the patient'sliver is raised to a temperature range, a duration, and a number oftimes sufficient to reduce or eliminate the patient's viral load of HCV.In embodiments of the invention, the temperature of the liver is raisedby local, regional, or intraperitoneal hyperthermia. In addition, theliver can be heated by the methods for raising the core temperature thatare described herein.

[0029] Conventional hyperthermia equipment can be used in the methods ofthe invention.

[0030] A number of different tests are used to determine if a person hasbeen infected with hepatitis C. In many people, the first indication ofa possible infection is an increase in the enzyme found in healthy livercells called alanine aminotransferase (ALT) and aspartateaminotransferase (AST). If there are more of these enzymes in the bloodthan normal, it often means that liver damage is occurring.

[0031] Clinicians will also test specifically for the hepatitis C virus.One set of tests looks for the presence of antibodies to the hepatitis Cvirus. If the antibodies (also referred to as anti-HCV) are present in aperson's blood, it usually means that the person has been infected withthe hepatitis C virus.

[0032] Other tests that are frequently performed detect the presence ofHCV RNA. The two tests that are used to measure HCV RNA are called thereverse transcriptase-polymerase chain reaction (RT-PCR) test and thebranched chain DNA (bDNA) test. RT-PCR is a more sensitive test and candetect much lower amounts of the virus than the bDNA test. The bDNA testcan detect large numbers of the virus in the blood, but cannot detectthe virus if only a low amount of the virus is present. One bDNA test isthe Chiron Quantiplex HCV-RNA 2.0 test, available from ChironDiagnostics, Inc., Emeryville, Calif. One RT-PCR test is Amplicor HCVMonitor test, available from Roche Diagnostics, Molecular SystemsDivision, Nutley, N.J.

EXAMPLES

[0033] Two HIV/AIDS patients who were co-infected with hepatitis C andwere failing or had failed HIV and HCV pharmaceutical therapies weretreated. The patients received a single session of Extracorporeal WholeBody Hyperthermia (EWBH). The patients continued their HIV drug regimensuntil the hyperthermia treatment and discontinued their drug regimensfor the treatment and follow-up period.

[0034] The two patients were failing pharmaceutical therapy, as definedby (A) an HIV PCR viral load ≧10,000 on a stable antiviral regimen, and(B) the failure of two or more combination antiviral regimens composedof all three of the following categories: two nucleoside analogues, onenon-nucleoside reverse transcriptase inhibitor and one proteaseinhibitor. The patients underwent a single hyperthermic treatment inwhich their core body temperature was raised to a maximum of 41.8±0.2°C. for 90 minutes.

[0035] The results of the EWBH treatments of the two patients arepresented in Table 2. TABLE 2 TREATED PATIENT DATA INTERVAL DATE HIVViral CD4 CK-MB HCV PATIENT ID (days) Load Lymphocytes CD4% BillirubinPlatelets Ratio ALT AST Viral Load PATIENT 1 Baseline 0  60,961 108 201.0 94,000 ND 95 73 14.3 Day 1 1 249,289 100 25 1.4 21,000 1.0 325  421 ND Days 3-7 3 100,641 72 30 1.1 43,000 ND 531  186  38.3 Unscheduled 24 69,021 102 12 ND 80,000 ND 100  64 8.38 Month 1 33  37,813 112 13 0.9147,000  ND 97 65 5.26 Unscheduled 45  70,632 133 14 0.9 109,000  ND 9774 7.32 Month 2 59  62,044 111 14 0.7 108,000  ND 88 75 1.36 Unscheduled73 150,142 123 15 1.2 76,000 ND 78 57 0.65 Unscheduled 88 196,237 101 111.4 87,000 ND NA NA <0.20  Unscheduled 102 134,415 NA NA NA NA ND NA NA<0.20  Month 4 Month 6 PATIENT 2 Baseline 0 157,599 7 2 0.4 cancelled-NA 60 82 1.1 hemolzed Day 1 1 410,332 4 3 0.7 cancelled- NA 214  439 11.7 hemolzed Days 3-7 3 619,376 9 6 1.4 34,000 NA 125  199  14.0 Month1 Month 2 Month 4 Month 6

[0036] The data in Table 2 show a dramatic decrease in the HCV viralload. The HCV viral load of Patient 1 decreased from 14.3 MEq/mL to lessthan 0.20 MEq/mL (the limit of the sensitivity of the test) in threemonths. The HCV viral load of the patients was determined with a ChironQuantiplex HCV-RNA 2.0 test, which uses a branched DNA signalamplification method, and is available from Chiron Diagnostics, Inc.,Emeryville, Calif. Both Patients 1 and 2 will be tested until six monthsfrom the date of the EWBH treatment or protocol failure. Patient 1 wason a regimen of lamivudine, indinavir, ritonavir, hydroxyurea, adetovir,and abacavir before the EWBH (this regimen was stopped during the trial)and used the following propylactic drugs during the trial: ibuprofen forlyme disease. Patient 2 was on a regimen of lamivudine and efavirenzbefore the EWBH (this regimen was stopped during the trial) and used thefollowing propylactic drugs during the trial: VALTREX for herpes, PEPCIDfor reflux, alprazolam for anxiety, and BACTRIM for Pneumocystis cariniipneumonia. Table 2 also provides the HIV viral load (copies/mL), CD4lymphocytes count (cells/mm³), CD4%, bilirubin (mg/dL), platelets count(cells/mm³), CK-MB ratio of intracellular enzymes, ALT (U/L), and AST(U/L).

[0037] According to the preferred embodiment, the two patients will bescreened for subsequent hyperthermic treatment as follows. The patientswill be followed until they experience a confirmed 0.5 log or greaterincrease in HIV viral load either (1) from baseline, if no decline inviral load is achieved after receiving EWBH, or (2) from the lowestrecorded HIV viral load following EWBH. In the event a patientexperiences a confirmed 0.5 log or greater increase in HIV viral load,they will be re-screened for eligibility of EWBH, and if eligible, willbe offered another single session of EWBH and followed per protocol. Thecriteria for re-treatment will be a 0.5 log increase in HIV viral loadabove baseline or nadir, whichever is greater. The details of theclinical protocol followed for the two patients and the equipment usedare presented below.

Clinical Protocol

[0038] The purpose of this investigation was to assess the efficacy of asingle EWBH treatment in individuals who were failing pharmaceuticaltherapies for HIV. Failing pharmaceutical therapies is defined as (A) anincrease in HIV PCR viral load to ≧10,000 while on a stable antiviralregimen, and (B) the failure any two combination antiviral regimenscomposed of all three of the following categories: two nucleosideanalogues, one non-nucleoside reverse transcriptase inhibitor and oneprotease inhibitor. A stable antiviral regimen is defined as no changesin antiretroviral regimen for sixteen weeks prior to screening for thestudy. Antiviral regimens will usually give peak PCR lowering within 8to 16 weeks after initiation.

[0039] In the event a patient experiences a confirmed 0.5 log or greaterincrease in viral load from baseline or nadir, they will be re-screenedfor eligibility for EWBH, and if eligible, will be offered anothersingle session of EWBH and followed per protocol. All patients will haveblood work drawn and analyzed at screening, during treatment, and atfollow-up as per protocol. The criteria for re-treatment will be a 0.5log increase in viral load above baseline or nadir, whichever isgreater.

[0040] Analysis of primary objective parameters included HIV viralloading as measured by Polymerase Chain Reaction (PCR), HIV-RNA, and CD4cell counts and percentages. Secondary objective parameters included theassessment of the cumulative incidence of opportunistic infections inthe EWBH treated verses the control populations. Clinical utility, dataassessing quality of life, were followed to evaluate significance ofthis treatment, pre and post therapy.

[0041] Prophylactic medication was allowed during the protocol periodand appropriate treatment was given for opportunistic infections.Prophylactic medication to minimize the risk for recurrent Herpesinfection was allowed. Any HIV/AIDS physical lesions present prior totherapy was measured and, if possible, photographed so that theselesions can be followed post treatment.

[0042] Patients fulfilled the following criteria to be eligible and hadno ineligibility exclusions:

[0043] 1. Documentation of positive test for Human ImmunodeficiencyVirus (HIV-1) Enzyme Linked Immunosorbent Assay (ELISA), confirmed byWestern Blot.

[0044] 2. Were failing recommended pharmaceutical therapy as defined by(A) an HIV PCR viral load of ≧10,000 while on a stable antiviral regimen(defined as no changes in antiretroviral regimen for sixteen weeks priorto screening for the study), (B) the failure of at least two combinationantiviral regimens composed of 2 or more antiretroviral medications, and(C) prior use of at least two nucleoside analogues, one non-nucleosidereverse transcriptase inhibitor, and one protease inhibitor.

[0045] 4. Karnofsky Performance status: ≧70%.

[0046] 5. Male or female, age 18-60 years old, inclusive.

[0047] 6. Granulocyte ≧500/mm3; White Blood Count (WBC) ≧1500/mm³;platelet count ≧100,000/mm³; hematocrit ≧30 vol %, and hemoglobin ≧10g/dl.

[0048] 7. Prothrombin Time (PT), Activated Partial Thromboplastin Time(aPTT), antithrombin III, fibrinogen, and thrombin time ≦20% of upper orlower limits of normal range.

[0049] 8. Serum creatinine <2.0 mg/dL.

[0050] 9. Serum aspartate aminotransferase (SGOT, AST) and Serum alanineaminotransferase (SGPT, ALT) ≦5× upper limit of normal.

[0051] 10. Negative pregnancy test for females.

[0052] 11. CD4+ lymphocyte helper cells ≦500 cells/mm³.

[0053] 12. Roche Amplicor HIV-1 RNA PCR ≧10,000 copies/ml.

[0054] 13. Signed informed consent.

[0055] 14. Stress Echocardiogram, or stress test and echocardiogram, orechocardiogram nucleotide studies with EF ≧45%, normal LV function andno evidence of coronary artery disease.

[0056] 15. Forced Expiratory Volume (FEV1) ≧60% of expected function.

[0057] 16. Negative CT scan of the brain with contrast.

[0058] 17. Willingness to adhere to follow-up schedule.

[0059] Patients that exhibited any of the following were excluded fromthe protocol:

[0060] 1. New York Heart Association (NYHA) classification III or IV.

[0061] 2. History of a myocardial infarction, abnormal stress testsuggesting ischemic changes, malignant, uncontrollable arrhythmia's ordocumented unstable angina within the last 12 months.

[0062] 3. Major surgery within four weeks of protocol therapy.

[0063] 4. History of central nervous system hemorrhage attributable tobleeding diathesis, or previously documented cerebrovascular accident.

[0064] 5. Evidence of any active opportunistic infection. Patient mustbe at least four weeks status post therapy for opportunistic infection.

[0065] 6. Allergic history to heparin, protamine, pork/beef products,fish, lidocaine or other anesthetic agents.

[0066] 7. Uncontrolled hypertension, systolic BP 160 and diastolic BP105.

[0067] 8. Active illicit drug use determined by history.

[0068] 9. Currently enrolled in other investigational clinical trialthat would preclude participation in this protocol.

[0069] In the preferred embodiment, patients receiving EWBH treatmentwould continue their current drug regimens until EWBH treatment and thendiscontinue their drug regimens for the treatment and follow-up period.All EWBH-treated patients were be followed until they experienced aconfirmed 0.5 log or greater increase in viral load either (1) frombaseline, if no significant decline in viral load was achieved afterreceiving EWBH, or (2) from the lowest recorded viral load followingEWBH. In the event an EWBH patient experienced a confirmed 0.5 log orgreater increase in viral load from baseline or nadir, they werere-screened for eligibility of EWBH, and if eligible, were offeredanother single session of EWBH and followed per protocol. All patientswere followed per protocol with serial collection of subjective andobjective data. All data was be accumulated, tabulated and analyzed.

[0070] For purposes of analysis, all patients (EWBH and Control)remained on study until: (1) criteria for treatment is documented (≧0.5log increase in PCR from baseline or nadir); (2) end of the six-monthfollow-up following initial randomization; or (3) loss to follow-up,withdrawal, or death during six-month follow-up.

[0071] Analysis of primary objective parameters included HIV viral loadas measured by Roche Amplicor HIV-RNA PCR, available from RocheDiagnostics, Nutley, N.J., lymphocyte subset profile and percentages(CD4). Secondary objective parameters included the assessment of thecumulative incidence of opportunistic infections in the patients.Clinical utility, data assessing quality of life were followed toevaluate significance of this treatment, pre and post therapy. Theobserved risks (i.e., device-related and treatment related adverseevents) of EWBH were monitored in relation to the potential benefits ofthe therapy.

[0072] Each patient was informed of all procedures to insure that therewould be compliance with the visits required for treatment and for thefollow-up process. Patients received the best available care for medicalproblems arising during the study. Current medications were noted at thetime of screening and reported on the case report form. Drugsadministered or taken during the trial were recorded on the case reportform, specifying the type of medication, dose, schedule, duration andreason for its use. All hospital admissions, clinic/office visits,incidence of opportunistic infections, including treatment given andduration, were closely monitored and recorded on Serious Adverse Event(SAE) and Adverse Event (AE) forms.

[0073] Clinical history included the date of HIV/AIDS diagnosis, historyof symptoms (dates and severity), and therapies previously administered,with duration of use and reasons for discontinuation. The historyincluded all known allergies.

[0074] Clinical assessment included blood studies as listed in Table ofRequired Observations. Follow-up bloods were obtained at Day 1 post EWBHtherapy and were repeated at follow-up clinic visits at day 3-7, months1, 2, 4, and 6 months (±1 week) (to the extent that the patient hadreached these time points).

[0075] The following studies were performed in addition to the physicalexamination. Pre-procedure blood sampling was obtained on the morning ofadmission. Additional tests were repeated throughout the study (seeTable of Required Observations). Tests and procedures were repeated asnecessary to assess clinical toxicity.

[0076] 1. Hematology:

[0077] Complete Blood Count (CBC, including WBC) with differential

[0078] Blood type (ABO Rh)

[0079] 2. Coagulation:

[0080] Prothrombin time (PT), Partial thromboplastin time (aPTT),Antithrombin III, Thrombin time, Fibrinogen

[0081] 3. General chemistries:

[0082] Sodium, Potassium, Chloride, CO₂, Calcium, Phosphorous,Magnesium, Glucose, Albumin, Creatinine, Cholesterol, Total protein,ALT, AST, Total bilirubin, Alkaline phosphatase, CreatininePhosphokinase (CPK), Lactate Dehydrogenase (LDH), Blood Urea Nitrogen(BUN),

[0083] 4. Cardiac assessment:

[0084] Stress Echocardiogram with Electrocardiogram (EKG)

[0085] 5. Pulmonary assessment:

[0086] Chest X-ray (CXR), Pulmonary Function Tests (1 Second ForcedExpiratory Volume, FEVI, and Forced Vital Capacity, FVC)

[0087] 6. Renal Function:

[0088] BUN, Creatine

[0089] 7. Neurologic assessment:

[0090] Thorough neurological physical examination

[0091] Computed Axial Tomography (CAT) scan with contrast of the head

[0092] 8. Immune system assessment:

[0093] Lymphocyte phenotype profile, including CD4, and CD8.

[0094] HIV RNA PCR (Roche Amplicor).

[0095] 9. Chronic Hepatitis assessment:

[0096] Hep C Qual. PCR

[0097] Hep B Surface antigen

[0098] HepB DNA PCR (if HBSAg positive)

[0099] 10. Measurement and documentation of any lesions, if appropriateby photographs.

[0100] 11. Measure of overall Karnofsky performance status TABLE OFREQUIRED OBSERVATIONS Days^(1,2) Months^(1,2) Test/ProcedureSCREEN^(1,2) 0 1 3 1 2 4 6 Consent Form(s) X ELISA / Western Blot X HIVRNA PCR level X X X X X X X X CD4/CD8 level X X X X X X X X HepC Qual.PCR X  X**  X** Hep C bDNA (Bayer)   X***   X***   X***   X***   X***  X***   X***   X*** HepBSAg X HepB DNA PCR**** X X X X X X X X HIVGenotype X X History and Physical X X X X X X X X CXR X Hematology X X XX X X X X Blood Type X Coagulation X X X X X X X X Biochemical Profile XX X X X X X X Cardiac Assessment X Pulmonary Assessment X Urine Analysis& Culture X Neurologic Assessment X Karnofsky Status X X X X X X X LymphNode Biopsy³ X X X X Spinal Fluid Specimen⁴ X X X X Health StatusQuestionnaire X X X X X X

[0101] The following protocol design was used in the hyperthermictreatment arm.

[0102] A. Pre Procedure:

[0103] After the history, physical examination, and laboratoryprocedures had been completed, and entry criteria satisfied, the patientwas admitted to the hospital on the day of the procedure. Bloods weredrawn according to the Table of Required Observations. Patient wasNothing Per Os (NPO) for at least 6 hours prior to the procedure.Preoperative antibiotics were given prophylactically for 24 hours.

[0104] B. Procedural Parameters:

[0105] Once in the Operating Room (OR) or treatment room s/he was placedupon the OR table and prepared for the procedure.

[0106] 1. Description of Treatment Facility:

[0107] The OR or treatment room used for the procedure DID not have tobe modified for this procedure. The operating table was equipped with afoam rubber mattress and/or pads for flexor point protection.

[0108] 2. Patient Instrumentation for EWBH:

[0109] The following was placed in the operating room prior to EWBH:

[0110] i. Swan-Ganz EKG lead monitoring

[0111] ii. Peripheral intravenous (IV) lines (2),

[0112] iii. Radial artery catheter

[0113] iv. Pulmonary artery (Swan-Ganz type) thermistor catheter viacentral vein.

[0114] v. Oximeter.

[0115] vi. Urinary bladder catheter with thermistor.

[0116] vii. Rectal temperature probe.

[0117] viii Esophageal temperature probe (general anesthesia).

[0118] ix Tympanic temperature.

[0119] x. Bilateral femoral venous catheters was placed by a surgeon andconnected to the hyperthermia unit

[0120] Temperature probes (esophageal, rectal, and tympanic) werecalibrated, within 0.1° C., to a NIST traceable device.

[0121] 3. Anesthesia:

[0122] Anesthetic management was the responsibility of theanesthesiologist administered appropriate agents according to thestandard of care. The choice of anesthetic agent was determined based onindividual patient profile. Either general anesthesia or sedative agentscan be used.

[0123] To ensure an adequate hourly urine volume, a dopamine drip at 2-3mcg/kg/min was used throughout the procedure and in the earlypostoperative period. Average urinary flow of 30 cc/hr minimum wastargeted. Fluid replacement during the procedure was administered at thediscretion of the operating team. Albumin and mannitol were not usedduring the hyperthermia treatment.

[0124] 4. EWBH conduct, all parameters were entered on case reportforms:

[0125] From the Swan Ganz catheter, serial readings of pulmonarysystolic and diastolic pressures and blood temperature were recorded.Cardiac output (CO) as measured via the thermodilution catheter wasmeasured prior to and following the treatment.

[0126] Each patient was continuously monitored at 5 minute intervals fortemperature during the procedure. The perfusionist recorded allperfusion data on specific perfusion data forms. Other patientparameters were recorded on standard OR flow sheets.

[0127] Temperatures Monitored:

[0128] Rectal (T_(R)), Esophageal(T_(E)), Tympanic (T_(P)), PulmonaryArtery (T_(PA)), Water Inlet/Heat Exchanger (T_(W)), Blood Outlet/HeatExchanger (T_(Bld))

[0129] a. Preparation:

[0130] The perfusionist primed the circuit with an isotonic solution,and circulated until totally de-aired. The surgeon cannulated thefemoral veins using open or percutaneous methods for connection with theextracorporeal circuit.

[0131] A predetermined dose of heparin required for extracorporealcirculatory bypass was calculated at 150 units/kg and administered intwo 75 unit/kg doses with an Activated Clotting Time (ACT) determinationbefore and after each dose. An ACT 2½ to 3 times normal was maintainedduring EWBH. Further doses of heparin, if needed, were administeredaccording to ACT measurement.

[0132] b. Heating Phase:

[0133] The time to reach a core temperature of 41.8°±0.2 was about 40minutes.

[0134] i. EWBH was initiated at a blood flow rate of approximately <20%of the baseline cardiac output. The water circulating through the heatexchanger did not exceed 50° C. for longer than 5 minutes.

[0135] ii. When either T_(E) or T_(R) (whichever is greater) reached41.8°±0.2° C., the plateau phase was begun.

[0136] iii. When 40.0° C. is reached, ice packs were placed under and/oraround the patient's neck.

[0137] c. Plateau Phase:

[0138] i. Core body temperature (T_(E), or T_(R), whichever is greater)was maintained between 41.6-42.0° C. for 90 minutes. T_(W) was reducedso that neither T_(E) or T_(R) exceeded 42.0° C. Since body temperaturecannot be instantaneously changed, momentary excursions above 42.0° C.were not be considered protocol deviations.

[0139] ii. Blood flow was altered to regulate blood and coretemperature.

[0140] d. Cooling Phase:

[0141] Anticipated time to reach 39° C. is 30-45 minutes.

[0142] i. Cooling was initiated at first by discontinuing the water flowfor the first 20 minutes, cooling by ambient heat loss.

[0143] ii. After 20 minutes the thermostat was reset to 30° C., and thewater flow re-instituted.

[0144] iii. When T_(R) reached 39° C., bypass was discontinued.

[0145] iv. Decannulated and reversed heparin with protamine sulfate.

[0146] e. Once stable, the patient was transferred to the postanesthesia or recovery room. REQUIRED OBSERVATIONS DURING EWBH BY PHASEWarming Plateau Cooling Test* Pre/ 0 15 30 45 0 15 30 45 60 75 90 15 30Post Blood gases X X X X X X X X X X X X X X Electrolytes X X X X XBiochemistry X X Hematology X X Urine Analysis & Culture X CD4/CD8 X HIVRNA PCRX Hep C bDNA (Bayer)** X Hep B DNA PCR*** X HIV-1 Genotype XCoagulation X X ACT only X X X X X X X X X X X X X X X Cardiac output XX Urine output X X Pressure Arterial X X Pulmonary X X EKG X XTemperature X X CXR X Lymph Node Bx¹ X Lumbar Puncture² X

[0147] C. Post-EWBH Patient Monitoring:

[0148] 1. In the Post Anesthesia or Recovery Room, standard monitoringincluded:

[0149] Continuous EKG monitoring

[0150] 12 lead EKG strip if indicated

[0151] Temperature, pulse, respirations and blood pressures (every 15minutes for the first one and one-half hours, then every half hour forthe next one and one-half hours),

[0152] Urinary output

[0153] 2. At the time of discharge from the hospital, a CXR was obtainedto rule out the presence of pulmonary problems such as pneumothorax,atelectasis, etc. Pressure dressing was removed from the femoralcannulation sites to confirm hemostasis.

[0154] 3. Patients were discharged from the hospital when able toambulate approximately 23 hours after admission.

[0155] Follow-up Visits

[0156] Follow-up visits were required at day 1 between day 3-7, and 1month (±7 days), 2 months (±7 days), 4 months (±7 days), and 6 months(±7 days) after the EWBH treatment (to the extent the patient hadreached these time points). At follow-up visits the patient wasquestioned about possible adverse reactions since their last visit, andany reaction described was recorded on the case report form. Blood wasdrawn for clinical laboratory tests according to the Table of RequiredObservations.

Equipment Used

[0157] The contents of the following U.S. patents and patentapplications are hereby incorporated by reference into this application:(1) U.S. Pat. No. 5,391,142, issued Feb. 21, 1995, and entitled“Apparatus and Method for the Extracorporeal Treatment of the Blood of aPatient Having a Medical Condition,” (2) U.S. Pat. No. 5,674,190, issuedOct. 7, 1997, and entitled “Extracorporeal Whole Body Hyperthermia UsingAlpha-Stat Regulation of Blood pH and pCO₂,” (3) U.S. patent applicationSer. No. 09/334,224, filed Jun. 16, 1999, entitled “Bladder Catheter forHyperthermia System,” and (4) U.S. patent application Ser. No.09/334,520, filed Jun. 16, 1999, entitled “Thermal Sensor forHyperthermia System”.

[0158] The hyperthermia equipment used was composed of three maincomponents: (a) the console, (b) a heater/cooler unit and (c) thedisposable blood contact circuit.

[0159] The console was composed of an extracorporeal, centrifugal pumpdevice used for the operating and monitoring of the hyperthermiaprocedure. It contained the drive motor and controllers for the pump andelectronics for monitoring the system parameters (temperature, pressure,and flow). The heater/cooler unit was used to raise or lower thepatient's temperature and maintain a desired patient temperature throughconductive heat transfer. Heated water was circulated through the heatexchanger to elevate the patient's temperature. Cool water wascirculated through the heat exchanger to reduce the patient'stemperature.

[0160] The disposable blood contact circuit was comprised of componentsfor inducing and monitoring hyperthermia. In order to complete thecircuit, vascular access was required. Blood left the patient via avenous cannula and PVC tubing which directed it to a centrifugal pump.From the pump, the blood was propelled through the heat exchanger wherethermal exchange occurred, with the assistance of the heater/cooler.After the blood was heated it passed through a blood filter beforereturning to the patient via a second venous cannula. Circuittemperature was monitored by a calibrated thermistor probe placed withinthe outlet of the heat exchanger. This represented the highest bloodtemperature reading in the circuit. The blood temperature and thosetemperatures recorded from the heater/cooler as well as patienttemperatures were the basis of the perfusion management of blood flowand heater/cooler temperature during the procedure.

[0161] Circuit flow was measured by an electrically isolatedelectromagnetic flowmeter built into the console, and a flow insert thatwas located in the blood circuit. Flow rates values have been determinedexperimentally to be approximately <20% of the baseline cardiac output.At these flow levels the rate of temperature rise to the patient wasgradual enough not to cause biochemical parameters to changedrastically. Blood flow rate adjustment was used with water bathtemperature adjustment to fine tune the process and maintain the corebody temperature within a narrow range for the appropriate time.

[0162] Circuit pressure monitoring was accomplished by the pressureelectronics built into the console and a disposable transducer which waslocated at the input side of the heat exchanger. This position withinthe circuit allowed the operator to monitor resistance to flowdownstream of the pump. Changes in the pressure reading were used as adiagnostic tool to determine circuit integrity and the state ofanticoagulation. A connection was made between the three-way stopcock,at the transducer, and the two-way stopcock at the pump input. With thethree-way stopcock turned to isolate the pump inlet pressure, theoperator was able to recognize a possible malposition of the egresscannula. By utilizing this reading in conjunction with the pulmonaryartery diastolic pressure it was possible to anticipate changes in thepatient's volume status. A 40 μm filter kept blood free of particulatematter.

[0163] The system was used to perform hyperthermia treatment of thepatient's blood. The components and sub-assemblies were consolidated andcoordinated to facilitate implementation of use. The apparatus includedstructures which defined an extracorporeal blood flow circuit. Such acircuit included a first cannula for use in cannulating a femoral veinof the patient. Such a cannula defined a blood egress point. A secondcannula was used for cannulating a different femoral vein of thepatient, and the second cannula defined a blood ingress point. Adiscontinuous conduit was provided to interconnect, in part, the firstand second cannulae. A conduit portion of an integrated, sterile modulehad interposed therein a pump, a heat exchanger for regulating thetemperature of blood flowing through the conduit portion, and sensorsfor ascertaining the temperature, pressure, and flow rate of bloodpassing through the conduit portion. The apparatus, further, employed acontroller for regulating the pump and temperature regulators inresponse to temperature, pressure, and blood flow rates sensed by thesensors.

[0164] A console was employed with the module having various controls.Such controls were used for selectively changing settings to achievedesired pressure and blood flow rate through the conduit portion.

[0165] The integrated, sterile module was a disposable component. As aresult, the medical treatment facility inhibited the possibility ofcontamination of the blood of one patient by HIV positive blood of apatient previously treated, and of health care workers involved in thetreatment.

[0166] In cannulating a patient for extracorporeal blood circulation, ablood flow circuit was defined between a first point of cannulation at avein of the patient and a second point of cannulation at a vein of thepatient. The patient's blood was then pumped through the circuit. As theblood passed through the circuit, it was heated to a first elevatedtemperature for a relatively short period of time. Thereafter, it washeated to a second elevated temperature, lower than the first elevatedtemperature, for a more extended period of time.

[0167] In an embodiment of the invention, the blood is heated to a firstelevated temperature of between 42° C. to 48° C. The blood could,typically, be maintained at the first elevated temperature for a periodof time of about one half to one hour. Thereafter, the blood could bemaintained at the second elevated temperature for a period of about oneto two hours. The second elevated temperature, it is envisioned, couldbe between 42 to 44° C. or 37° C. to 39° C.

[0168] Referring now to the drawings wherein like reference numeralsdenote like elements through the several views, FIG. 2 showsdiagrammatically the apparatus 10 used in the hyperthermia treatment ofthe patients as a procedure for addressing hepatitis C infection. InFIG. 2, a femoral vein in the left leg was cannulated as a point ofegress of blood from the patient's body (as at 16), and a femoral veinin the patient's right leg was cannulated as a point of ingress of theblood back into the patient (as at 18). It will be understood that thesetwo specific points of cannulation 16, 18 are not exclusive and thatother cannulation locations are specifically contemplated. The locationsillustrated in FIG. 2, however, have been found to be particularlyappropriate, and ingress and egress points in different legs have beenshown as being utilized so that a single leg of the patient is notcompromised.

[0169]FIG. 2 illustrates the series blood flow circuit 14 which includedfirst and second cannulae for cannulating the patient at two veins, aspreviously discussed. A conduit 24 having a discontinuity therein wasprovided to interconnect, in part, the first and second cannulae. Anintegrated, sterile module 26, as best seen in FIG. 1, was interfacedwith the discontinuity in the discontinuous conduit 24 to complete theseries blood flow circuit 14. The module 26 contained all of thecomponents which were exposed to blood in the course of a treatment. Itincluded a conduit portion 28 which was placed in communication withsegments 30 of the discontinuous conduit 24 to complete the circuit 14.

[0170] The conduit portion 28 of the disposable module 26 had differentcomponents interposed therein. Blood was pumped from the egress point 16of cannulation at a vein to a heat exchanger 32 by means of a pump 34 ofappropriate construction. FIG. 2 illustrates the centrifugal pump 34that was used, but it will be understood that this specific type of pumpis not exclusive.

[0171]FIG. 2 illustrates a heat exchanger 32 down-flow from the pump 34.The heat exchanger 32 functioned to selectively elevate the temperatureof the blood to a desired level. The blood, after passing through theheat exchanger 32, passed through a perfusate filter 36. At thislocation, the perfusate can be purged of any impurities.

[0172] A flow probe or sensor 38 was in the series flow circuit 14down-flow from the perfusate filter 36. The probe 38 served to senseinformation with regard to the measure of flow rate of the perfusatepassing through the circuit 14. FIG. 2 illustrates the pressuretransducer 40 that was used in the circuit 14 down-flow from the flowsensor 38. While it is important to know flow rate of the perfusatethrough the circuit 14, it is also important to know the pressurethrough the system also. Consequently, the patient being treated can beadequately protected.

[0173]FIG. 2 also illustrates the temperature sensor 42 that was used inthe circuit 14. The sensor 42, of course, served to provide informationwith regard to the temperature of the blood flowing through the circuit14.

[0174]FIG. 2 also shows a branch 44 of the circuit 14 which recirculatedexcess perfusate, not needed to be fed back into the patient, back tothe pump 34 for recirculation. The recirculation branch 44 was also usedduring initial setup.

[0175] Also illustrated are a series of tubing clamps 46. Such clamps 46serve, basically, as occluders which can be disposed to pinch tubingsegments to preclude flow therethrough. In FIG. 2, the three such tubingclamps 46 that were used are illustrated. A first was immediatelydown-flow of the egress point on the patient. A second was locatedimmediately prior to the location at which the blood reenters thepatient's body. The third was positioned in the recirculation segment ofthe circuit 14.

[0176]FIG. 1 illustrates, as previously discussed, an integrated,sterile module 26 in which are disposed all of the components describedwith reference to FIG. 2 as being exposed to blood in the blood flowcircuit 14. FIG. 1 also, however, illustrates the non-disposable baseunit that was used including a chassis 60 which removably mounts theintegrated, sterile module 26. FIG. 1 further shows that the base unitincluded a console or controller unit 62 for controlling operation ofthe hyperthermia procedure being performed. The console 62 functioned toregulate and maintain perfusate flow rate, pressure, and temperature atdesired levels.

[0177] The console 62 had a series of digital display windows 64. Suchwindows 64 read temperature, pressure, and flow rate and displayed thoseparameters for both actual sensed values and inputted alarm rangesettings. Each display 64 was provided with a series of visual alarms(i.e., LED's 66) for signaling when, for example, a desired range withinwhich temperature, flow rate, or pressure, is intended to be maintained,was exceeded. A series of alarm setting controls 68 were also shown asbeing provided. Each window 64 had corresponding upper and lower rangecontrols and an intermediately positioned toggle switch 70. The toggleswitch 70 could be toggled between positions representative of upper andlower range settings. When in an upper range setting, for example, theappropriate dial 72 could be maneuvered to adjust the upper range limit.

[0178] Finally, the control panel 74 of the console 62 had a lower rowof dials, displays, etc. These components included a timer 76, rate andamplitude controls 78 for additional modes of operation (such as apulsatile mode), and an electronic filter 80 for filtering aberrantamplitude signals regarding, for example, pressure in the circuit 14,etc.

[0179] In the structure illustrated in FIG. 1 and used to treat thepatients, it is intended that the heater/cooler (not shown) forproviding external fluid to the heat exchanger 32 would not comprisepart of the console 62. Heat exchange was implemented in a collateralmanner known in the prior art.

[0180] While not specifically shown in FIG. 1, the console 62 containedtherewithin a motor 82 which interfaces, through a wall, with theperfusate pump 34. This was done by providing the motor 82 with amagnetic rotor. As the motor 82 was driven, the rotor was caused to berotated also. A magnetic element was provided in the pump 34, and such amagnetic element interfaced, through the wall, with the magnetic rotor.Driving of the rotor, in turn, translated to operation of the pump 34 toa desired level.

[0181]FIG. 3 illustrates schematically how the pump 34, was controlledin response to pressure and flow rate levels sensed by respectivesensors 38, 40. Those figures show the integrated, sterile module 26 andthe components enclosed therewithin by a dotted line.

[0182] In utilizing the system for hyperthermia treatments, the patientwas cannulated in the manner discussed above. Initially, the patient wasout of the circuit 14, and flow bypassed the patient. This was effectedby manipulation of the appropriate tube clamps 46 to effect flow throughthe bypass branch circuit 44.

[0183] A selector switch 84 was manually positioned so that feedback wasprovided from either the motor 82, the pressure transducer 40, or theflow probe 38. Input from the appropriate feedback component passedthrough the selector switch 84 to a servo-amplifier 86. The amplifier86, in turn, inputted information to control the pump speed in anappropriate fashion to accomplish desired flow and pressure parameters.

[0184]FIG. 3 also illustrates a variable resistor 88 which wasmanipulated in initiating the setting of a particular parameter. Theparameter was set and, after the system was appropriately calibrated,the patient was introduced into the flow system 14. Thereafter,continuous monitoring was performed of temperature, pressure, and flowrate. If the alarm system indicated that a parameter had gone outsidethe desired range, appropriate action was taken to bring the parameterback within the range.

[0185] During hyperthermia, pCO₂ varies directly with a change in bodytemperature. It is desirable to hold the bloods CO₂ content constantduring alpha-stat regulation, thereby requiring an inverse relationshipbetween air convection requirements and body temperature. Alpha-statmaintains constant CO₂ by regulating pCO₂. Hence, utilizing thealpha-stat technique for blood gas management is advantageous in thatthe pH gradient across the cellular membrane is preserved throughout therange of temperatures encountered during hyperthermia. This alpha-statregulation of blood pH and pCO₂ were used in treating the patients.

[0186] By direct control of pulmonary ventilation through manipulationof respiratory rate, the pCO₂, the total CO₂, and the pH were maintainedthroughout the procedure according to alpha-stat parameters, ensuringthat electrolyte balance was maintained throughout. No electrolytereplacement was required in any patient during the procedure, nor wasthere ever a need to administer sodium bicarbonate for metabolicacidosis.

[0187] The blood flow circuit comprised a Blood Gas Analyzer (BGA).Within the BGA is an analyzer which analyzes the blood gases, includingthe blood pH and pCO₂ through infrared or chemical analysis. A pulseoximeter attached to the patient through suitable means, measured thepO₂ of a patient's blood. The microprocessor then analyzed the dataassociated with the blood's pH, pCO₂, pO₂ and calculated the base excessof the blood normalized at 37° C. The microprocessor was programmed tothen automatically adjust the respiratory rate of the patient and eitherthe amount of NaHCO₃ or acidotic crystalloid solution (which affects theHCO₃ ⁻ ion concentration) being introduced into the patient's blood.This was accomplished by adjusting the respiratory rate of the patientthrough ventilation or medications.

[0188] The respiratory management of the blood at constant CO₂ content,while the temperature was changed, maintained a constant alpha therebystabilizing the biochemical reactions fundamental to the metabolicwelfare of components of the patient's blood. The sodium bicarbonatebuffering system was based upon the following equation:

H⁺+HCO₃ ⁻˜H₂CO₃˜H₂O+CO₂

[0189] Acidosis (↓pH) occurs when there is an increase of H+ (metabolic)and/or CO₂ (respiratory). Respiratory acidosis was treated with changesin depth of ventilation or ventilatory rate. Metabolic acidosis wastreated with the administration of sodium bicarbonate (NaHCO₃). “Bicarb”dissociates into Na+ and HCO₃ ⁻ which combines with H+ to form CO₂ andH₂O.

[0190] The blood gases, pH, pO₂, pCO₂, and HCO₃ ⁻ concentration wereobtained by direct measurement. Base excess (BE) is a derived parameterbased upon the relationship between the measured pCO₂, and HCO₃ ⁻concentration, and is calculated relative to the normal HCO₃ ⁻centration values: 24 mEq/L in arterial blood and 26 mEq/L in venousblood.

Optional Equipment That Was Not Used

[0191] A thermal sensor and bladder catheter that were not used to treatthe patients are described below.

Thermal Sensor

[0192] An improved temperature monitoring device suited toextracorporeal whole body hyperthermia can be used.

[0193] The sensor described is connected to the blood flow circuit nearthe patient. The temperature sensor has a very small mass and is placeon a strut. The strut places the thermal sensor in the laminar bloodflow of a duct or fitting. In this fashion, a fast reacting thermalassessment may be made of blood temperature as blood enters or leavesthe body.

[0194]FIG. 4 illustrates a temperature probe 133 for supporting thetemperature sensor 130 in the flow of blood moving through ahyperthermia system. As shown in FIG. 4, the probe 133 includes a tubeor flow-directing passage 140 having a wall defining an interior lumen141. Although a cylindrical shape is shown and is preferred to minimizewetted surface area, other cross-sectional shapes are operable. As shownin FIG. 4, the cross-sectional area of the lumen 141 remains constant inthe direction of flow indicated by arrow 138. It should be appreciatedthat the lumen 141 may decrease in cross-sectional area in the directionof flow to maintain laminar flow past the strut 134.

[0195] A temperature sensor 130 is attached to the strut 134.Preferably, the strut 134 is shaped and positioned such that the sensor30 supported thereon is placed in a region of laminar flow andpreferably near a location of maximum flow velocity. A region of laminarflow is illustrated in the velocity profile 136. More specifically, thestrut 134 is shaped and positioned such that at least a portion of strut134 lies upstream of the site at which the strut 134 attaches to orpasses through the tube 140. The preferred strut 134 has a generallyarcuate shape along its length. As shown in the embodiment illustratedin FIG. 4, the strut 134 has a terminating tip 145 that is positionednear the axial center of the tube 140 where the blood flow achievesmaximum velocity. In this fashion the sensor 130 is located in themaximum flow zone in the device and can sense subtle changes in bloodtemperature. By positioning the sensor “in-line”, or in the flow ofblood as it passes through the system, advantages are achieved. Forexample, the laminar flow prevents disruption of the blood andtemperature change due to mixing. This factor combined with the fastresponse small thermal mass sensor 130 improves control of bodytemperature.

[0196] The preferred form of the probe 133 includes fittings which maybe barbed. These allow the device to be positioned close to the patient.It is believed that monitoring in close proximity to the patient isdesirable to minimize heat loss to the environment.

[0197] More than one sensor can be used in a hyperthermic system. Theuse of a second sensor increases the ability of the system to accuratelymonitor and control temperature.

[0198] The sensors 130 and 132 may be of any temperature-sensing type,such as thermistors, thermocouples, and the like.

Bladder Catheter

[0199] An improved catheter can be used in the whole body hyperthermiasystem. In use, the catheter is suspended in the bladder of the patient.A cuff on the catheter inflates after the catheter is inserted in thebladder to assist in positioning and securing the catheter. The catheterhas a temperature sensor proximal of the inflatable cuff to measure bodytemperature at the urinary sphincter muscle. The sensor is locatedrelative to the cuff a distance know to generally correspond to thetypical distance between the bladder and the sphincter muscle in humans.This distance is known to be approximately the same amongst humansregardless of size.

[0200] In an alternative catheter, a second temperature sensor is placeddistal of the inflatable cuff and thus monitors the temperature of theurine pool in the bladder. Each of the measurements from the first andsecond temperature sensors has a different time constant depending onthe volume of urine in the bladder, and the level of perfusion in thesphincter. Data from these two sensors, the differences between thereadings, and the time-dependent variation of these two sensors cancontribute to the overall efficacy of the device.

[0201] An exemplary version of the bladder catheter is shown in thefigures in which like reference numerals refer to equivalent structurethroughout.

[0202]FIG. 5 shows a bladder temperature probe 230 having an elongatebody 244 and terminating in a proximal end 246 and further having adistal tip 248 and a first temperature sensor 232, which may be of anyconventional type, including thermistors, thermocouples or other solidstate temperature sensors. A drainage lumen 236 communicates with adistal opining 238 to allow fluid to be withdrawn from the bladder 231or to allow fluid, such as saline, to be infused into the bladder. Aninflatable distal cuff 240 positions the catheter and prevents itsremoval from the bladder while the cuff is inflated. The sensor 232 andthe inflatable cuff are spaced and oriented such that when theinflatable cuff 240 holds the probe 230 in position in the patient'sbladder 231, the sensor 232 is located proximal of the urinary sphinctermuscle 242. Temperature information gathered at this site from thesurrounding tissue is likely to be reliable and somewhat less subject torapid fluctuation than a temperature reading taken from other locations,such as the urine pool.

[0203] In an alternate catheter, illustrated in FIG. 6, the cathetercarries a second temperature sensor 234. In practice, the cuff positionsthe second temperature sensor 234 in the bladder urine or fluid poolwhile the first sensor 232 is located adjacent the musculature near thesphincter 242. It is expected that the two sensors will vary in measuredtemperature as the effective time constants for the two locationsdiffer. These two temperatures and relative rates of their variationcontribute to the efficacy of body temperature control.

[0204] Computerized controls can be added to all of the equipmentdescribed above.

[0205] The above description is provided for the purpose of describingembodiments of the invention and is not intended to limit the scope ofthe invention in any way. It will be apparent to those skilled in theart that various modifications and variations can be made withoutdeparting from the spirit or scope of the invention. Thus, it isintended that the present invention cover the modifications andvariations of this invention provided they come within the scope of theappended claims and their equivalents.

What is claimed is:
 1. A method for treating a patient infected withhepatitis C virus (HCV) comprising raising the core temperature of thepatient and then returning the core temperature of the patient to normalat least one time, wherein the core temperature is raised to atemperature range and a duration sufficient to reduce or eliminate thepatient's viral load of HCV.
 2. The method of claim 1, wherein the coretemperature of the patient is raised and returned to normal one time. 3.The method of claim 1, wherein the core temperature of the patient israised and returned to normal two or more times.
 4. The method of claim1, wherein the core temperature is raised by circulating the patient'sblood from the patient, through an extracorporeal blood flow circuit,and back to the patient, wherein the blood returned to the patient hasbeen heated within the blood flow circuit to an elevated temperaturerange.
 5. The method of claim 4, wherein the patient's blood iscirculated from the patient through a blood vessel and returned to thepatient through a blood vessel.
 6. The method of claim 4, wherein thepatient's blood is circulated from the patient through a vein andreturned to the patient through a vein.
 7. The method of claim 4,wherein the patient's blood is circulated from the patient through anartery and returned to the patient through a vein.
 8. The method ofclaim 1, wherein the core temperature is raised by inserting a heatingelement into the patient and wherein the heating element heats thepatient's blood.
 9. The method of claim 8, wherein the heating elementis inserted into a blood vessel of the patient.
 10. The method of claim1, wherein the core temperature is raised to a temperature range of from38 to 48° C.
 11. The method of claim 1, wherein the core temperature israised to a temperature range of from 38 to 44° C.
 12. The method ofclaim 1, wherein the core temperature is raised to a temperature rangeof from 41.8 to 42.2° C.
 13. The method of claim 10, wherein the coretemperature is measured rectally.
 14. The method of claim 10, 11, or 12,wherein the core temperature is raised for a period of from 2 minutes tosixteen hours.
 15. The method of claim 10, 11, or 12, wherein the coretemperature is raised for a period of from one-half to three hours. 16.The method of claim 10, 11, or 12, wherein the core temperature israised for a period of from one to two hours.
 17. The method of claim10, 11, or 12, wherein the core temperature is raised for a period offrom 80 to 100 minutes.
 18. The method of claim 1, 4 or 8, wherein thepatient's viral load of HCV is determined at least once before the coretemperature has been raised said at least one time.
 19. The method ofclaim 1, 4 or 8, wherein the patient's viral load of HCV is determinedat least once after the core temperature has been raised and returned tonormal said at least one time.
 20. The method of claim 1, 4 or 8,wherein the patient's viral load of HCV is determined at least twodifferent times after the core temperature has been raised and returnedto normal said at least one time.
 21. The method of claim 1, 4 or 8,wherein the patient's viral load of HCV is reduced by 30 percent or moreone month after the core temperature has been raised and returned tonormal said at least one time.
 22. The method of claim 1, 4, or 8,wherein the patient's viral load of HCV is reduced by 50 percent or moreone month after the core temperature has been raised and returned tonormal said at least one time.
 23. The method of claim 1, 4, or 8,wherein the patient's viral load of HCV is reduced by 75 percent or moreone month after the core temperature has been raised and returned tonormal said at least one time.
 24. The method of claim 1, 4, or 8,wherein the patient's viral load of HCV is reduced by 90 percent or moreone month after the core temperature has been raised and returned tonormal said at least one time.
 25. The method of claim 1, 4, or 8,wherein the patient's viral load of HCV is reduced by 95 percent or moreone month after the core temperature has been raised and returned tonormal said at least one time.
 26. The method of claim 1, 4, or 8,wherein the patient's viral load of HCV is reduced to less than thesensitivity level of a branched DNA signal amplification test one monthafter the core temperature has been raised and returned to normal saidat least one time.
 27. The method of claim 1, 4, or 8, wherein thepatient's viral load of HCV is reduced to less than the sensitivitylevel of a reverse transcriptase-polymerase chain reaction test onemonth after the core temperature has been raised and returned to normalsaid at least one time.
 28. The method of claim 1, 4, or 8, wherein thepatient's viral load of HCV is reduced by 30 percent or more threemonths after the core temperature has been raised and returned to normalsaid at least one time.
 29. The method of claim 1, 4, or 8, wherein thepatient's viral load of HCV is reduced by 50 percent or more threemonths after the core temperature has been raised and returned to normalsaid at least one time.
 30. The method of claim 1, 4, or 8, wherein thepatient's viral load of HCV is reduced by 75 percent or more threemonths after the core temperature has been raised and returned to normalsaid at least one time.
 31. The method of claim 1, 4, or 8, wherein thepatient's viral load of HCV is reduced by 90 percent or more threemonths after the core temperature has been raised and returned to normalsaid at least one time.
 32. The method of claim 1, 4, or 8, wherein thepatient's viral load of HCV is reduced by 95 percent or more threemonths after the core temperature has been raised and returned to normalsaid at least one time.
 33. The method of claim 1, 4, or 8, wherein thepatient's viral load of HCV is reduced to less than the sensitivitylevel of a branched DNA signal amplification test three months after thecore temperature has been raised and returned to normal said at leastone time.
 34. The method of claim 1, 4, or 8, wherein the patient'sviral load of HCV is reduced to less than the sensitivity level of areverse transcriptase-polymerase chain reaction test three months afterthe core temperature has been raised and returned to normal said atleast one time.
 35. The method of claim 1, further comprising treatingthe patient with a pharmaceutical indicated for hepatitis C.
 36. Themethod of claim 35, wherein the patient is treated with a singlepharmaceutical indicated for treating hepatitis C.
 37. The method ofclaim 35, wherein the patient is treated with two or morepharmaceuticals indicated for treating hepatitis C.
 38. The method ofclaim 35, wherein the pharmaceutical is administered before raising thecore temperature of the patient said at least one time.
 39. The methodof claim 35, wherein the pharmaceutical is administered while the coretemperature of the patient is raised.
 40. The method of claim 35,wherein the pharmaceutical is administered after the core temperature ofthe patient has been raised and returned to normal said at least onetime.
 41. The method of claim 35, wherein the pharmaceutical isadministered: (i) before raising the core temperature of the patientsaid at least one time; (ii) while the core temperature of the patientis raised; (iii) after the core temperature of the patient has beenraised and returned to normal said at least one time; or (iv)combinations thereof.
 42. The method of claim 35, wherein thepharmaceutical is administered before raising the core temperature ofthe patient said at least one time, while the core temperature of thepatient is raised, and after the core temperature of the patient hasbeen raised and returned to normal said at least one time.
 43. Themethod of claim 35, wherein the pharmaceutical is selected frominterferons, protease inhibitors, cytokines, or any combination ofantiviral drugs.
 44. The method of claim 35, wherein the pharmaceuticalis selected from ribavirin, lamivudine, interferon alfacon-1, interferonalfa-2a, interferon alfa-2b, interferon-alfa-n1, thymosin alpha-1,interleukin-2, interferon alpha-n3, ketoprofen, interferon beta-1a,interferon gamma-1b, interleukin-12, histamine dihydrochloride,thymalfasin, zidovudine, didanosine, zalcitabine, stavudine, abacavar,nevirapine, delaviridine, efavirenz, ritonavir, indinavir, nelfinavir,saquinavir, amprenavir, or combinations thereof.
 45. The method of claim35, wherein the pharmaceutical is selected from an interferon,ribavirin, or lamivudine.
 46. The method of claim 35, wherein thepharmaceutical is an alpha interferon.
 47. The method of claim 1, 4, or8, wherein the patient has an acute HCV infection.
 48. The method ofclaim 1, 4, or 8, wherein the patient has a chronic HCV infection. 49.The method of claim 1, 4, or 8, wherein the patient is co-infected witha pathogen.
 50. The method of claim 49, wherein the pathogen is a virus.51. The method of claim 49, wherein the pathogen is a spirochete orbacterium.
 52. The method of claim 50, wherein the virus is a heatlabile virus.
 53. The method of claim 52, wherein the heat labile virusis selected from herpesviruses, hepadnaviruses, togaviruses,flaviviruses, coronaviruses, rhabdoviruses, filoviruses,paramyxoviruses, othomyxoviruses, bunyaviruses, arenaviruses, orretroviruses.
 54. The method of claim 52, wherein the heat labile virusis selected from HIV, hepatitis B virus, Ebstein-Barr virus,cytomegalovirus, or varicella-zoster virus.
 55. The method of claim 52,wherein the heat labile virus is HIV.
 56. The method of claim 51,wherein the pathogen is a spirochete selected from the genus treponema,borrelia, or leptospira.
 57. The method of claim 51, wherein thepathogen is a spirochete selected from Treponema pallidum, Treponemapertenue, Treponema carateum, Treponema pallidum endemicum, Borreliaburgdorferi, Borrelia hermsii, or Leptospira interrogans.
 58. A methodfor treating a patient infected with hepatitis C virus (HCV) comprisingraising the core temperature of the patient and then returning the coretemperature of the patient to normal at least one time, wherein the coretemperature is raised to a temperature range and a duration sufficientto reduce or eliminate the patient's viral load of HCV, and wherein thepatient is co-infected with HIV.
 59. The method of claim 58, wherein thecore temperature of the patient is raised and returned to normal onetime.
 60. The method of claim 58, wherein the core temperature of thepatient is raised and returned to normal two or more times.
 61. Themethod of claim 58, wherein the core temperature is raised bycirculating the patient's blood from the patient, through anextracorporeal blood flow circuit, and back to the patient, wherein theblood returned to the patient has been heated within the blood flowcircuit to an elevated temperature range.
 62. The method of claim 61,wherein the patient's blood is circulated from the patient through ablood vessel and returned to the patient through a blood vessel.
 63. Themethod of claim 61, wherein the patient's blood is circulated from thepatient through a vein and returned to the patient through a vein. 64.The method of claim 61, wherein the patient's blood is circulated fromthe patient through a artery and returned to the patient through a vein.65. The method of claim 58, wherein the core temperature is raised byinserting a heating element into the patient and wherein the heatingelement heats the patient's blood.
 66. The method of claim 65, whereinthe heating element is inserted into a blood vessel of the patient. 67.The method of claim 58, wherein the core temperature is raised to atemperature range of from 38 to 48° C.
 68. The method of claim 58,wherein the core temperature is raised to a temperature range of from 38to 44° C.
 69. The method of claim 58, wherein the core temperature israised to a temperature range of from 41.8 to 42.2° C.
 70. The method ofclaim 67, wherein the core temperature is measured rectally.
 71. Themethod of claim 67, 68, or 69, wherein the core temperature is raisedfor a period of from 2 minutes to sixteen hours.
 72. The method of claim67, 68, or 69, wherein the core temperature is raised for a period offrom one-half to three hours.
 73. The method of claim 67, 68, or 69,wherein the core temperature is raised for a period of from one to twohours.
 74. The method of claim 67, 68, or 69, wherein the coretemperature is raised for a period of from 80 to 100 minutes.
 75. Themethod of claim 58, 61, or 65, wherein the patient's viral load of HCVis determined at least once before the core temperature has been raisedsaid at least one time.
 76. The method of claim 58, 61, or 65, whereinthe patient's viral load of HCV is determined at least once after thecore temperature has been raised and returned to normal said at leastone time.
 77. The method of claim 58, 61, or 65, wherein the patient'sviral load of HCV is determined at least two different times after thecore temperature has been raised and returned to normal said at leastone time.
 78. The method of claim 58, 61, or 65, wherein the patient'sviral load of HCV is reduced by 30 percent or more one month after thecore temperature has been raised and returned to normal said at leastone time.
 79. The method of claim 58, 61, or 65, wherein the patient'sviral load of HCV is reduced by 50 percent or more one month after thecore temperature has been raised and returned to normal said at leastone time.
 80. The method of claim 58, 61, or 65, wherein the patient'sviral load of HCV is reduced by 75 percent or more one month after thecore temperature has been raised and returned to normal said at leastone time.
 81. The method of claim 58, 61, or 65, wherein the patient'sviral load of HCV is reduced by 90 percent or more one month after thecore temperature has been raised and returned to normal said at leastone time.
 82. The method of claim 58, 61, or 65, wherein the patient'sviral load of HCV is reduced by 95 percent or more one month after thecore temperature has been raised and returned to normal said at leastone time.
 83. The method of claim 58, 61, or 65, wherein the patient'sviral load of HCV is reduced to less than the sensitivity level of abranched DNA signal amplification test one month after the coretemperature has been raised and returned to normal said at least onetime.
 84. The method of claim 58, 61, or 65, wherein the patient's viralload of HCV is reduced to less than the sensitivity level of a reversetranscriptase-polymerase chain reaction test one month after the coretemperature has been raised and returned to normal said at least onetime.
 85. The method of claim 58, 61, or 65, wherein the patient's viralload of HCV is reduced by 30 percent or more three months after the coretemperature has been raised and returned to normal said at least onetime.
 86. The method of claim 58, 61, or 65, wherein the patient's viralload of HCV is reduced by 50 percent or more three months after the coretemperature has been raised and returned to normal said at least onetime.
 87. The method of claim 58, 61, or 65, wherein the patient's viralload of HCV is reduced by 75 percent or more three months after the coretemperature has been raised and returned to normal said at least onetime.
 88. The method of claim 58, 61, or 65, wherein the patient's viralload of HCV is reduced by 90 percent or more three months after the coretemperature has been raised and returned to normal said at least onetime.
 89. The method of claim 58, 61, or 65, wherein the patient's viralload of HCV is reduced by 95 percent or more three months after the coretemperature has been raised and returned to normal said at least onetime.
 90. The method of claim 58, 61, or 65, wherein the patient's viralload of HCV is reduced to less than the sensitivity level of a branchedDNA signal amplification test three months after the core temperaturehas been raised and returned to normal said at least one time.
 91. Themethod of claim 58, 61, or 65, wherein the patient's viral load of HCVis reduced to less than the sensitivity level of a reversetranscriptase-polymerase chain reaction test three months after the coretemperature has been raised and returned to normal said at least onetime.
 92. A method for treating a patient infected with hepatitis Cvirus (HCV) comprising raising the temperature of the patient's liverand then returning the temperature of the patient's liver to normal atleast one time, wherein the temperature of the patient's liver is raisedto a temperature range and a duration sufficient to reduce or eliminatethe patient's viral load of HCV.
 93. The method of claim 92, wherein thetemperature of the liver is raised by local, regional, orintraperitoneal hyperthermia.